rs142883891

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_033380.3(COL4A5):c.1289C>A(p.Ala430Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,208,648 control chromosomes in the GnomAD database, including 12 homozygotes. There are 2,014 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A430V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0042 ( 2 hom., 152 hem., cov: 23)

Exomes 𝑓: 0.0053 ( 10 hom. 1862 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.89

Publications

7 publications found

Variant links:

Genes affected

COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

COL4A5 Gene-Disease associations (from GenCC):

Alport syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, G2P
X-linked Alport syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

COL4A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_033380.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 538 curated pathogenic missense variants (we use a threshold of 10). The gene has 138 curated benign missense variants. Gene score misZ: 2.4995 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.00821501).

BP6

Variant X-108591181-C-A is Benign according to our data. Variant chrX-108591181-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 256277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00417 (469/112598) while in subpopulation NFE AF = 0.00582 (310/53233). AF 95% confidence interval is 0.00529. There are 2 homozygotes in GnomAd4. There are 152 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.1289C>A	p.Ala430Asp	missense_variant	Exon 20 of 53	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL4A5	ENST00000328300.11 link	c.1289C>A	p.Ala430Asp	missense_variant	Exon 20 of 53	1	NM_033380.3	ENSP00000331902.7	P29400-2
COL4A5	ENST00000483338.1 link	c.113C>A	p.Ala38Asp	missense_variant	Exon 4 of 20	1		ENSP00000495685.1	Q49AM6
COL4A5	ENST00000361603.7 link	c.1289C>A	p.Ala430Asp	missense_variant	Exon 20 of 51	2		ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes

AF:

0.00417

AC:

469

AN:

112547

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000709

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00159

Gnomad ASJ

AF:

0.00977

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00218

Gnomad FIN

AF:

0.0135

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00582

Gnomad OTH

AF:

0.00330

GnomAD2 exomes

AF:

0.00465

AC:

851

AN:

182887

AF XY:

0.00507

show subpopulations

Gnomad AFR exome

AF:

0.000229

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0119

Gnomad NFE exome

AF:

0.00563

Gnomad OTH exome

AF:

0.00222

GnomAD4 exome

AF:

0.00527

AC:

5778

AN:

1096050

Hom.:

Cov.:

AF XY:

0.00514

AC XY:

1862

AN XY:

362324

show subpopulations

African (AFR)

AF:

0.000532

AC:

AN:

26338

American (AMR)

AF:

0.00148

AC:

AN:

35165

Ashkenazi Jewish (ASJ)

AF:

0.00909

AC:

176

AN:

19354

East Asian (EAS)

AF:

0.00

AC:

AN:

30197

South Asian (SAS)

AF:

0.00427

AC:

231

AN:

54046

European-Finnish (FIN)

AF:

0.00989

AC:

401

AN:

40526

Middle Eastern (MID)

AF:

0.00165

AC:

AN:

3026

European-Non Finnish (NFE)

AF:

0.00553

AC:

4656

AN:

841438

Other (OTH)

AF:

0.00529

AC:

243

AN:

45960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

215

429

644

858

1073

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

352

528

704

880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00417

AC:

469

AN:

112598

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

152

AN XY:

34782

show subpopulations

African (AFR)

AF:

0.000707

AC:

AN:

31109

American (AMR)

AF:

0.00158

AC:

AN:

10730

Ashkenazi Jewish (ASJ)

AF:

0.00977

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3542

South Asian (SAS)

AF:

0.00219

AC:

AN:

2738

European-Finnish (FIN)

AF:

0.0135

AC:

AN:

6156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00582

AC:

310

AN:

53233

Other (OTH)

AF:

0.00326

AC:

AN:

1533

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00456

Hom.:

178

Bravo

AF:

0.00337

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00588

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00699

AC:

ExAC

AF:

0.00500

AC:

607

EpiCase

AF:

0.00562

EpiControl

AF:

0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Jul 09, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31144478, 8940267) -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL4A5: BS1, BS2 -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 07, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COL4A5 c.1289C>A (p.Ala430Asp) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0047 in 182887 control chromosomes, including 342 hemizygotes and 1 homozygote in the general population (gnomAD). The variant was predominantly at a frequency of 0.0056 within the Non-Finnish European subpopulation in the gnomAD database, including 175 hemizygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.21 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A5 causing Alport Syndrome 1, X-Linked Recessive phenotype (0.0046), strongly suggesting that the variant is a benign polymorphism. Six ClinVar submitters have assessed the variant since 2014: five have classified the variant as benign and one as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala430Asp in exon 20 of COL4A5: This variant is not expected to have clinical significance because it has been identified in 1.17% (53/4522) of Finnish chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142883891). -

X-linked Alport syndrome

Benign:2

Dec 03, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 08, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.47

.;T;T

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.75

T;T;T

MetaRNN

Benign

0.0082

T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.14

N;N;.

PhyloP100

1.9

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.5

N;N;.

REVEL

Benign

0.20

Sift

Benign

0.29

T;T;.

Sift4G

Benign

0.51

T;T;.

Polyphen

0.0090, 0.0

.;B;B

Vest4

0.070

MVP

0.56

MPC

0.45

ClinPred

0.018

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.44

gMVP

0.37

Mutation Taster

=83/17

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over